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Republic of Turkey Ministry of Health Clinical Research Project


Immunosuppressive Effects of Mesenchymal Stromal Cell Infusion in Small Intestinal Transplant Patients

Republic of Turkey Ministry of Health Clinical Research Projects

Intestinal transplantation is used more frequently for irreversible gastrointestinal failure patients who no longer can be maintained on TPN (Total Parenteral Nutrtion) or effectively treated for complex abdominal pathology. Short bowel syndromes, gut dysmotility, gasstrointestinal neoplastic syndromes and enterocyte dysfunction are the leading causes of gut failure and indications for transplantation (1). Furthermore, the survival advantages of the procedure have significantly improved over the last 5 years, because of novel immunosuppressive protocols, better postoperative management, and new surgical innovations (2). Stem cell plasticity refers to the ability of organ-specific stem cells from one tissue to produce cells of a different lineage and tissue. For example, adult bone marrow cells may be able to engraft into other tissues and differentiate into cell types specific to that organ, such as hepatocytes, skeletal myocytes or small intestine(LGR5+) (3). There is increasing evidence to support this hypothesis, especially from observations that Y-chromosome containing cells can be seen in the tissues of female recipients of bone marrow from male donors (4). Although it has been argued that this may represent cell fusion rather than stem cell plasticity.(5)

In the small and large intestine, bone marrow engraftment and differentiation into mesenchymal cells have been demonstrated in humans and mice. The possibility that bone marrow derived cells could be used to populate and regenerate intestinal mucosais clearly exciting and of particular relevance to the field of tissue engineering.(6)

SBS (small bowell syndrome) is the most common indication for intestineonly transplantation. Congenital disorders such as gastroschisis, volvulus, and atresia are the leading causes in children. In adults, the main causes are visceral ischemia, Crohn’s disease, trauma, mesenteric desmoid tumor, and surgical adhesions (7). Intestinal morphology reflects its role as an absorptive surface and a barrier against luminal contents. Small intestinal surface area is increased about 600-fold by a combination of micro- and macroscopic features (8). Both small and large intestinal mucosal surfaces are rapidly replaced as a result of the activity of stem cells found in the intestinal crypts (9). Understanding of stem cell dynamics and signaling has increased rapidly in recent years (10). Tissue engineering of intestinal mucosa has been performed in animal models and offers the possibility of a novel therapy for patients with short bowel syndrome (7). The morphology of the intestine reflects its two principle roles: the digestion and absorption of nutrients, and the maintenance of a barrier against the external environment. The basic macroscopic and microscopic structure of the small and large intestine and will review current understanding of the role of stem cells in intestinal regeneration.(11) An improved knowledge of stem cell biology has led to the production of tissue engineered intestine and progress in this exciting field will be explored.

There are five main epithelial cell lineages, all of which are derived from stem cells in the intestinal crypts. The most plentiful cells in the mucosal epithelium are columnar enterocytes, which make up the absorptive surface of the intestine. The apical surface of these cells consists of a layer of densely packed microvilli, visible with electron microscopy. Each enterocyte has about 3,000 microvilli on its apical surface and their presence increases small intestinal surface area about 20- fold. Intestinal enterocytes contain numerous transport proteins in their apical and basal membranes, which allow active and passive transport of nutrients from the gut (12). In addition, several digestive enzymes, such as disaccharidases, are bound to the enterocyte microvilli. Paneth cells, unlike the other epithelial cell lines, are found at the crypt bases. They are characterised by granules containing lysozyme, tumour necrosis factor-α and defensins, and are believed to play an antibacterial role. Finally, M cells are believed to be involved in antigen sampling and transportation (13). The lamina propria contains a wide range of cell types including smooth muscle cells, vascular endothelial cells and fibroblasts.(7)

There is a particular interest on the intestinal subepithelial myofibroblasts. These cells are located in proximity to the mucosal epithelium and are believed to produce growth factors, including hepatocyte growth factor, which promote proliferation of the intestinal epithelial stem cells (12).

In the immunsuppressive era, immunomodulatory strategies in the form of graft or donor pretreatment were already used in intestinal transplant recipeints, in an attempt to prolong graft survival (14). The Pittsburgh group and, later, the Miami group continued to give unmodified donor bone marrow infusions for about a decade but this strategy failed to significantly improve outcome (15-17).

Specifically, clinical results failed to show that bone marrow augmentation reduced the incidence of acute or chronic rejection; the question of whether chimerism plays a role in the development and maintenance of tolerance has not been conclusively answered (27-29). Intestinal transplantation will be more broadly applied only if immunosuppressive or immunodulatory stragtegies are developed that diminish or eliminate the rate of severe, exfoliative rejection with its associated risks of graft loss and recipient death.

Over the last decade, there has been a rising interest in the use of mesenchymal stem cells (MSCs) for clinical applications.(18-20). There is a lot of study about using LGR5+ stem cell and rejenerative medicine in the small intestine transplantation (21). Despite recent clinical trials investigating the use of MSCs in treating immune-mediated disease (22). their applicability in solid-organ transplantation is still unknown (23-24). Whereas, from other clinical studies, it would appear that administration of MSCs is safe, issues like dosing, timing, route of administration, and in particular the use of autologous or donor-derived MSCs may be of crucial importance for the functional outcome of MSCs treatment in organ transplantation. (25-28) In this study we try to show the high selective immunsuppressive effects of autologous or/and allogenic LGR5+ MSCs treatment in small bowel transplantation in humans.


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  22. Tian H, Biehs B, Warming S, Leong K. G., Langell L, Klein O D, de Sauvage F. J., A reserve stem cell population in small intestine renders LGR5 positive cells dispensable, Nature, 2011 Sep 18; 478 (7368): 255-9: doi:10.1038/nature 10408
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